Process for producing amine derivatives

ABSTRACT

This invention provides a convenient and industrially advantageous process producing amine derivatives having the action of inhibiting the secretion and accumulation of amyloid beta protein.In Compound (I), the ether linkage is selectively cleaved without cleaving the amide linkage present in the same molecule and tertiary amines are not converted into quaternary salts, and thus Amine Derivative (V) with good qualities having the action of inhibiting the secretion and accumulation of amyloid beta protein can be obtained in high yield.

This application is the National Phase filing of International PatentApplication No. PCT/JP01/02845, filed Apr. 2, 2001.

TECHNICAL FIELD

This invention relates to a convenient process for producing aminederivatives having the action of inhibiting the secretion andaccumulation of amyloid β protein and useful as a pharmaceuticalpreparation, as well as useful synthetic intermediates thereof.

BACKGROUND ART

As amine derivatives having the action of inhibiting the secretion andaccumulation of amyloid β protein and a process for producing the aminederivatives, the following process is described in JP-A 11-80098.

[formula]

wherein W represents a hydrogen atom or a protective group, Xarepresents an oxygen atom etc., Y represents an optionally substituteddivalent C₁₋₆ aliphatic hydrocarbon group (excluding methylene) whichmay be bound via an oxygen atom or a sulfur atom, R¹ and R² eachrepresent a S hydrogen atom or an optionally substituted lower alkyl, ormay, together with their adjacent nitrogen atom, form an optionallysubstituted nitrogen-containing heterocyclic ring, ring A represents abenzene ring which may further have a substituent group, ring Brepresents a 4- to 8-membered ring which may further have a substituentgroup, Ar represents an optionally substituted ring-assembled aromaticgroup or an optionally substituted condensed aromatic group, Xbrepresents a bond etc., and L represents an leaving group or hydroxy.

In the process described above, the amide moiety of Compound (IVa) isreduced to give Compound (Va), and then the ether linkage is cleaved togive Compound (IIa). This is because, when an amide linkage and an etherlinkage are present in the same molecule, selective cleavage of theether linkage is generally difficult and thus the amide linkage is alsosimultaneously cleaved.

In the above process, it was revealed that in the step of subjectingCompound (IIa) to alkylation reaction to form Compound (Ia), thetertiary amine is also alkylated to form a quaternary amine salt, thuscausing a reduction in the yield of the desired amine derivative.

There is demand for development of a convenient and industriallyadvantageous process for producing an amine derivative having the actionof inhibiting the secretion and accumulation of amyloid β protein.

BRIEF DESCRIPTION OF DRAWING

FIG. 1 shows a powdery X-ray crystal diffraction pattern of crystalsobtained in Example 1.

SUMMARY OF INVENTION

As a result of extensive study, the present inventor found that acompound represented by the formula:

wherein R represents an optionally substituted hydrocarbon group, R¹ andR² each represent a hydrogen atom or an optionally substituted C₁₋₆alkyl group, or may, together with their adjacent nitrogen atom, form anoptionally substituted nitrogen-containing heterocyclic ring, ring Arepresents an optionally substituted benzene ring, ring B represents anoptionally substituted 4- to 8-membered ring, and Y represents anoptionally substituted divalent C₁₋₆ aliphatic hydrocarbon group whichmay have an oxygen atom or a sulfur atom, or a salt thereof isselectively cleaved at the ether linkage thereof, to produce a compoundrepresented by the formula:

wherein the symbols have the same meanings as defined above, then thisproduct is reacted with a compound represented by the formula:

X—L  (III)

wherein X represents an optionally substituted hydrocarbon group or anoptionally substituted cyclic group, and L represents an leaving groupor a hydroxyl group, to produce a compound represented by the formula:

wherein the symbols have the same meanings as defined above, and thenthis compound is subjected to reduction reaction, whereby the desiredcompound represented by the formula:

wherein the symbols have the same meanings as defined above, or a saltthereof can be produced in high yield and high qualities withoutconverting the tertiary amine into a quaternary amine salt, and on thebasis of this finding, this invention was completed.

That is, the present invention provides:

(1) A process for producing a compound represented by the formula:

wherein R¹ and R² each represent a hydrogen atom or an optionallysubstituted C₁₋₆ alkyl group, or may, together with their adjacentnitrogen atom, form an optionally substituted nitrogen-containingheterocyclic ring, ring A represents an optionally substituted benzenering, ring B represents an optionally substituted 4- to 8-membered ring,and Y represents an optionally substituted divalent C₁₋₆ aliphatichydrocarbon group, or a salt thereof, comprising selectively cleavingthe ether linkage of a compound represented by the formula:

wherein R represents an optionally substituted hydrocarbon group and theother symbols have the same meanings as defined above, or a saltthereof;

(2) The process according to above-mentioned (1), wherein the etherlinkage is selectively cleaved in the presence of an acid and mercaptanor sulfide;

(3) The process according to above-mentioned (2), wherein the acid isLewis acid;

(4) The process according to above-mentioned (2), wherein the acid issulfonic acid;

(5) The process according to above-mentioned (1), wherein the etherlinkage is selectively cleaved in the presence of methanesulfonic acidand methionine;

(6) The process according to above-mentioned (1), wherein R is anoptionally substituted C₁,₆ alkyl or optionally substituted C₇₋₁₉aralkyl group;

(7) The process according to above-mentioned (1), wherein the etherlinkage of (+)-N,N-dimethyl-(6-methoxy-2-tetralin)acetamide isselectively cleaved, to produce(+)-N,N-dimethyl-(6-hydroxy-2-tetralin)acetamide;

(8) A process for producing a compound represented by the formula:

wherein R¹ and R² each represent a hydrogen atom or an optionallysubstituted C₁₋₆ alkyl group, or may, together with their adjacentnitrogen atom, form an optionally substituted nitrogen-containingheterocyclic ring, ring A represents an optionally substituted benzenering, ring B represents an optionally substituted 4- to 8-membered ring,X represents an optionally substituted hydrocarbon group or anoptionally substituted cyclic group, and Y represents an optionallysubstituted divalent C₁₋₆ aliphatic hydrocarbon group, or a saltthereof, comprising selectively cleaving the ether linkage of a compoundrepresented by the formula:

wherein R represents an optionally substituted hydrocarbon group and theother symbols have the same meanings as defined above, or a saltthereof, to produce a compound represented by the formula:

wherein the symbols have the same meanings as defined above, or a saltthereof, then reacting the same with a compound represented by theformula:

X—L

wherein X has the same meaning as defined above and L represents aleaving group or a hydroxyl group, to produce a compound represented bythe formula:

wherein the symbols have the same meanings as defined above, or a saltthereof, and then subjecting the same to reduction reaction;

(9) The process according to above-mentioned (8), wherein X is anoptionally substituted ring-assembled aromatic group or an optionallysubstituted condensed aromatic group;

(10) The process according to above-mentioned (8), which comprisesselectively cleaving the ether linkage of(+)-N,N-dimethyl-(6-methoxy-2-tetralin)acetamide, to produce(+)-N,N-dimethyl-(6-hydroxy-2-tetralin)acetamide, then reacting the samewith 4-chloromethylbiphenyl to produce(+)-N,N-dimethyl-(6-(4-biphenylyl)methoxy-2-tetralin)acetamide, and thensubjecting the same to reduction reaction, to produce(R)-(+)-6-(4-biphenylyl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralinhydrochloride monohydrate;

(11) A compound represented by the formula:

wherein R¹ and R² each represent a hydrogen atom or an optionallysubstituted C₁₋₆ alkyl group, or may, together with their adjacentnitrogen atom, form an optionally substituted nitrogen-containingheterocyclic ring, ring A represents an optionally substituted benzenering, ring B represents an optionally substituted 4- to 8-membered ring,and Y represents an optionally substituted divalent C₁₋₆ aliphatichydrocarbon group, or a salt thereof;

(12) The compound according to above-mentioned (11), which is(+)-N,N-dimethyl-(6-hydroxy-2-tetralin)acetamide;

(13) A compound represented by the formula:

wherein R¹ and R² each represent a hydrogen atom or an optionallysubstituted C₁₋₆ alkyl group, or may, together with their adjacentnitrogen atom, form an optionally substituted nitrogen-containingheterocyclic ring, ring A represents an optionally substituted benzenering, ring B represents an optionally substituted 4- to 8-membered ring,Y represents an optionally substituted divalent C₁₋₆ aliphatichydrocarbon group, and X represents an optionally substitutedhydrocarbon group or an optionally substituted cyclic group, or a saltthereof;

(14) The compound according to above-mentioned (13), which is(+)-N,N-dimethyl-(6-(4-biphenylyl)methoxy-2-tetralin)acetamide;

(15) A process for producing a compound represented by the formula:

wherein R¹ and R² each represent a hydrogen atom or an optionallysubstituted C₁₋₆ alkyl group, or may, together with their adjacentnitrogen atom, form an optionally substituted nitrogen-containingheterocyclic ring, ring A represents an optionally substituted benzenering, ring B represents an optionally substituted 4- to 8-membered ring,X represents an optionally substituted hydrocarbon group or anoptionally substituted cyclic group, and Y represents an optionallysubstituted divalent C₁₋₆ aliphatic hydrocarbon group, or a saltthereof, comprising allowing a compound represented by the formula:

wherein the symbols have the same meanings as defined above, or a saltthereof to react with a compound represented by the formula:

X—L

wherein X has the same meaning as defined above and L represents aleaving group or a hydroxyl group;

(16) A process for producing a compound represented by the formula:

wherein R¹ and R² each represent a hydrogen atom or an optionallysubstituted C₁₋₆ alkyl group, or may, together with their adjacentnitrogen atom, form an optionally substituted nitrogen-containingheterocyclic ring, ring A represents an optionally substituted benzenering, ring B represents an optionally substituted 4- to 8-membered ring,X represents an optionally substituted hydrocarbon group or anoptionally substituted cyclic group, and Y represents an optionallysubstituted divalent C₁₋₆ aliphatic hydrocarbon group, or a saltthereof, comprising allowing a compound represented by the formula:

wherein the symbols have the same meanings as defined above, or a saltthereof to react with a compound represented by the formula:

X—L

wherein X has the same meaning as defined above and L represents aleaving group or a hydroxyl group, to produce a compound represented bythe formula:

wherein the symbols have the same meanings as defined above, or a saltthereof and then subjecting the same to reduction reaction;

(17)(R)-(+)-6-(4-biphenylyl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralinhydrochloride monohydrate;

(18) The compound according to above-mentioned (15), which shows adiffraction pattern having characteristic peaks in spacings (d values)of approximately 23.1, approximately 5.17, approximately 4.72,approximately 4.56, approximately 4.38, approximately 4.10,approximately 3.93, approximately 3.74, approximately 3.16 andapproximately 3.09 angstrom by powder X-ray crystal diffraction;

(19) A pharmaceutical composition comprising the compoundabove-mentioned (17);

(20) The pharmaceutical composition according to above-mentioned (19),which is an agent for preventing or treating Alzheimer's disease;

(21) A method for preventing or treating Alzheimer's disease, whichcomprises incorporating the compound of above-mentioned (17) intomammals; and

(22) Use of the compound above-mentioned (17) for production of an agentfor preventing or treating Alzheimer's disease.

DETAILED DESCRIPTION OF THE INVENTION

In the formula above, the “hydrocarbon group” of the “optionallysubstituted hydrocarbon group” represented by R includes a C₁₋₆ alkylgroup (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl,isohexyl etc.), C₂₋₆ alkenyl group (e.g., vinyl, allyl, isopropenyl,2-butenyl etc.), C₂₋₆ alkynyl group (e.g., ethynyl, propargyl, 2-butynyletc.), C₃₋₆ cycloalkyl group (e.g., cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl etc.), C₆₋₁₄ aryl group (e.g., phenyl,1-naphthyl, 2-naphthyl, 2-indenyl, 2-anthryl etc.) and C₇₋₁₉ aralkylgroup (e.g., benzyl, phenethyl, diphenylmethyl, triphenylmethyl,1-naphthylmethyl, 2-naphthylmethyl, 2,2dipbenylethyl, 3-phenylpropyl,4-phenylbutyl, 5-phenylpentyl etc.).

In the “optionally substituted hydrocarbon group” represented by R, the“substituent group” includes a halogen atom (e.g., fluorine, chlorine,bromine, iodine etc.), C₁₋₃ alkylene dioxy (e.g., methylene dioxy,ethylene dioxy etc.), nitro, cyano, optionally halogenated C₁₋₆ alkyl,optionally halogenated C₃₋₆ cycloalkyl, optionally halogenated C₁₋₆alkoxy, optionally halogenated C₁₋₆ alkyl thio, hydroxy, amino,mono-C₁₋₆ alkyl amino (e.g., methylamino, ethylamino, propylamino,isopropylamino, butylamino etc.), di-C₁₋₆, alkyl amino (e.g.,dimethylamino, diethylamino, dipropylamino, dibutylamino,ethylmethylamino etc.), 5- to 7-membered saturated cyclic amino, formyl,carboxy, carbamoyl, C₁₋₆ alkyl-carbonyl (e.g., acetyl, propionyl etc.),C₁₋₆ alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, tert-butoxycarbonyl etc.), C₁₋₁₀ aryl-carbonyl (e.g.,benzoyl, 1-naphthoyl, 2-naphthoyl etc.), C₆₋₁₀ aryloxy-carbonyl (e.g.,phenoxycarbonyl etc.), C₇₋₁₆ aralkyloxy-carbonyl (e.g.,benzyloxycarbonyl, phenethyloxcarbonyl etc.), 5- to 6-memberedheterocyclic carbonyl (e.g., nicotinoyl, isonicotinoyl, 2-thenoyl,3-thenoyl, 2-furoyl, 3-furoyl, morpholinocarbonyl, piperidinocarbonyl,1-pyrrolidinylcarbonyl etc.), mono-C₁₋₆ alkyl-carbamoyl (e.g.,methylcarbamoyl, ethylcarbamoyl etc.), di-C₁₋₆ alkyl-carbamoyl (e.g.,dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl etc.), C₆₋₁₀aryl-carbamoyl (e.g., phenylcarbamoyl, 1-naphthylcarbamoyl,2-naphthylcarbamoyl etc.), 5- to 6-membered heterocyclic carbamoyl(e.g., 2-pyridylcarbamoyl, 3-pyridylcarbamoyl, 4-pyridylcarbamoyl,2-thienylcarbamoyl, 3-thienylcarbarnoyl etc.), C₁₋₆ alkyl sulfonyl(e.g., methylsulfonyl, ethylsulfonyl etc.), C₆₋₁₀ aryl sulfonyl (e.g.,benzenesulfonyl, 1-naphthalenesulfonyl, 2-naphthalenesulfonyl etc.),formyl amino, C₁₋₆ alkyl-carboxamide (e.g., acetaride etc.), C₆₋₁₀aryl-carboxamide (e.g., phenylcarboxamide, naphthylcarboxamide etc.),C₁₋₆ alkoxy-carboxamide (e.g., methoxycarboxamide, ethoxycarboxamide,propoxycarboxamide, butoxycarboxamide etc.), C₁₋₆ alkyl sulfonylamino(e.g., methylsulfonylamino, ethylsulfonylamino etc.), C₁₋₆alkyl-carbonyloxy (e.g., acetoxy, propanoyloxy etc.), C₆₋₁₀aryl-carbonyloxy (e.g., benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxyetc.), C₁₋₆ alkoxy-carbonyloxy (e.g., methoxycarbonyloxy,ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy etc.),mono-C₁₋₆ alkyl-carbamoyloxy (e.g., methylcarbamoyloxy,ethylcarbamoyloxy etc.), di-C₁₋₆ alkyl-carbamoyloxy (e.g.,dimethylcarbamoyl, diethylcarbamoyloxy etc.), C₆₋₁₀ aryl-carbamoyloxy(e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy etc.), nicotinoyloxy andC₆₋₁₀ aryloxy (e.g., phenyloxy, naphthyloxy etc.), and the number ofsubstituent groups is 1 to 5, preferably 1 to 3.

The “optionally halogenated C₁₋₆ alkyl” described above includes, forexample, C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) which may have 1 to5, preferably 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine,iodine etc.). Examples thereof include methyl, chloromethyl,difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl,2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,3,3-trifluoropropyl,isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl,6,6,6-trifluorohexyl etc.

The “optionally halogenated C₃₋₆ cycloalkyl” described above includes,for example, C₃₋₆ cycloalkyl (e.g., cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl etc.) which may have 1 to 5, preferably 1 to 3halogen atoms (e.g., fluorine, chlorine, bromine, iodine etc.). Examplesthereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,4,4-dichlorocyclohexyl, 2,2,3,3-tetrafluorocyclopentyl,4-chlorocyclohexyl etc.

The “optionally halogenated C₁₋₆ alkoxy” described above includes, forexample, C₁₋₆ alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, pentyloxyetc.) which may have 1 to 5, preferably 1 to 3 halogen atoms (e.g.,fluorine, chlorine, bromine, iodine etc.). Examples thereof includemethoxy, difluoromethoxy, trifluoromethoxy, ethoxy,2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy,4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.

The “optionally halogenated C₁₋₆ alkyl thio” described above includes,for example, C₁₋₆ alkyl thio (e.g., methylthio, ethylthio, propylthio,isopropylthio, butylthio, sec-butylthio, tert-butylthio etc.) which mayhave 1 to 5, preferably 1 to 3 halogen atoms (e.g., fluorine, chlorine,bromine, iodine etc.). Examples thereof include methylthio,difluoromethylthio, trifluoromethylthio, ethylthio, propylthio,isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio,hexylthio etc.

The “5- to 7-membered saturated cyclic amino” described above includes,for example, morpholino, thiomorpholino, piperazine-1-yl, 4-substitutedpiperazine-1-yl, piperidino, pyrrolidine-1-yl, hexamethylene-1-yl etc.

The “substituent group” of the “4-substituted piperazine-1-yl”,includes, for example, one or two substituent groups selected from C₁₋₆alkyl (e.g., methyl, ethyl- etc.), C₆₋₁₄ aryl (e.g., phenyl etc.), C₇₋₁₉aralkyl (e.g., benzyl etc.), 5- to 10-membered aromatic heterocyclicgroup (e.g., 2-, 3- or 4-pyridyl etc.) and acyl (e.g., formyl, acetyletc.).

R is preferably an optionally substituted C₁₋₆ alkyl or optionallysubstituted C₇₋₁₉ aralkyl group.

In the formula above, the “C₁₋₆ alkyl group” of the “optionallysubstituted C₁₋₆ alkyl group” represented by R¹ and R² includes methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl etc.

The “substituent group” and the number thereof for the “optionallysubstituted C₁₋₆ alkyl group” represented by R¹ and R² are exemplifiedby those for the “optionally substituted hydrocarbon group” representedby R described above.

In the “optionally substituted nitrogen-containing heterocyclic ring”which is formed by R¹ and R² together with their adjacent nitrogen atom,the “nitrogen-containing heterocyclic ring” includes, for example, a 3-to 8-membered nitrogen-containing heterocyclic ring which contains atleast one nitrogen atom other than carbon atoms and which may contain 1to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and anoxygen atom, and examples thereof include aziridine, azetidine,morpholine, thiomorpholine, piperidine, piperazine, pyrrolidine,hexamethyleneimine, heptamethyleneimine, or unsaturated cyclic aminesthereof (e.g., 1,2,5,6-tetrahydropyridine etc.). Among these,morpholine, piperidine, piperazine and pyrrolidine are preferred.

The “nitrogen-containing heterocyclic ring” in the “optionallysubstituted nitrogen-containing heterocyclic ring” may have 1 to 3substituent groups selected from the “substituent group” in the“optionally substituted hydrocarbon group”, oxo and C₇₋₁₉ aralkyl (e.g.,benzyl). Preferable substituent groups include, for example, C₁₋₆ alkyl(e.g., methyl, ethyl, propyl, isopropyl, butyl etc.), hydroxy, amino,mono-C₁₋₆ alkyl amino (e.g., methylamino, ethylamino, propylamino,isopropylamino, butylamino etc.), di-C₁₋₆ alkylamino (e.g.,dimethylamino, diethylamino, dipropylamino, dibutylamino,ethylmethylamino etc.), 5- to 7-membered saturated cyclic amino (e.g.,morpholino, piperazine-1-yl, piperidino, pyrrolidine-1-yl,hexamethyleneimine-1-yl etc.), C₁₋₆ alkyl-carboxamide (e.g., acetamideetc.), C₁-₆ alkoxy-carboxamide (e.g., methoxycarboxamide,ethoxycarboxamide etc.), an optionally substituted aromatic group (e.g.,C₆₋₁₀ aryl [preferably phenyl, 1- or 2-naphthyl] or a 5- to 6-memberedaromatic heterocyclic group [preferably 2-, 3- or 4-pyridyl] which mayhave 1 to 3 substituent groups selected from a halogen atom, cyano, C₁₋₆alkyl and C₁₋₆ alkoxy), oxo, etc.

R¹ and R² are preferably C₁₋₆ alkyl such as methyl.

In the formula above, the substituent group of the “optionallysubstituted benzene ring” represented by the ring A includes, forexample, a halogen atom (e.g., fluorine, chlorine, bromine, iodineetc.), optionally halogenated C₁₋₆ alkyl (e.g., C₁₋₆ alkyl which mayhave 1 to 5 halogen atoms described above), optionally halogenated C₁₋₆alkoxy (e.g., C₁₋₆ alkoxy which may have 1 to 5 halogen atoms describedabove), hydroxy, amino etc. The ring A may be substituted with one tothree of these substituent groups at substitutable positions other thanthe position of a group represented by the formula —OR, —OH or a grouprepresented by the formula —OX, and when the number of substituentgroups is 2 or more, the respective substituent groups may be the sameor different.

The ring A is preferably a benzene ring substituted with only a grouprepresented by the above formula —OR, —OH, or a group represented by theabove formula —OX.

In the “optionally substituted 4- to 8membered ring” represented by thering B in the formula above, the “4- to 8-membered ring” includes a 4 to8-membered homo- or heterocyclic ring which may contain one double bondat a portion other than the portion condensed with the ring A and whichmay contain 1 to 3 heteroatoms selected from an oxygen atom, a nitrogenatom and a sulfur atom other than carbon atoms. Examples thereof includea ring represented by the formula:

wherein, Z represents (i) a bond, (ii) C₁₋₄ alkylene, (iii) C₂₋₄alkenylene, (iv) —O—CH₂— (v) —O— CH₂—CH₂— or (vi) the formula —NR⁸—CH₂—or —NR⁸—CH₂—CH₂—, whereupon R⁸ represents a hydrogen atom, a anoptionally substituted hydrocarbon group, or acyl. R⁸ is preferably ahydrogen atom, optionally halogenated C₁₋₆ alkyl (e.g., C₁₋₆ alkyl whichmay have 1 to 5 halogen atoms described above), C₁₋₆ alkylcarbonyl(e.g., acetyl, propionyl etc.), C₁₋₆ alkoxy-carbonyl (e.g.,methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyletc.), C₆₋₁₀ aryl-carbonyl (e.g., benzoyl, 1-naphthoyl, 2-naphthoyletc.), C₆₋₁₀ aryloxy-carbonyl (e.g., phenoxycarbonyl etc.), C₇₋₁₆aralkyloxy-carbonyl (e.g., benzyloxycarbonyl, phenethyloxycarbonyletc.), 5- to 6-membered heterocyclic carbonyl (e.g., nicotinoyl,isonicotinoyl, 2-thenoyl, 3-thenoyl, 2-furoyl, 3-furoyl,morpholiocarbonyl, piperidinocarbonyl, 1-pyrrolidinylcarbonyl etc.),mono-C₁₋₆ alkyl-carbarnoyl (e.g., methylcarbamoyl, ethylcarbamoyl etc.),di-C₁₋₆ alkyl-carbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl,ethylmethylcarbamoyl etc.), C₆₋₁₀ aryl-carbamoyl (e.g., phenylcarbamoyl,1-naphthylcarbamoyl, 2-naphthylcarbamoyl etc.), 5- to 6-memberedheterocyclic carbamoyl (e.g., 2-pyridylcarbamoyl, 3-pyridylcarbamoyl,4-pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl etc.), C₁₋₆alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl etc.) and C₆₋₁₀arylsulfonyl (e.g., benzenesulfonyl, 1-naphthalenesulfonyl,2-naphthalenesulfonyl etc.). R⁸ is more preferably a hydrogen atom,optionally halogenated C₁₋₆ alkyl, C₁₋₆ alkyl-sulfonyl and C₁₋₃alkylsulfonyl.

Z is preferably C₁₋₃ alkylene, —NR⁸—CH₂— etc, and more preferablyethylene.

The “4- to 8-membered ring” is preferably a ring represented by theformula:

wherein Z has the same meaning as defined above. This ring is preferablya 6-membered homo- or heterocyclic ring which does not contain a doublebond in the other portion than the portion condensed with the ring A andwhich may contain one oxygen atom or imino other than carbon atoms.

In the “optionally substituted 4- to 8-membered ring” represented by thering B, the “substituent group” includes, for example, oxo, C₁₋₆ alkyl(e.g., methyl, ethyl, propyl, isopropyl, butyl etc.), hydroxy etc. Thering B may be substituted with one to three substituent groups atsubstitutable positions, and when the number of substituent groups is 2or more, the respective substituent groups may be the same or different.

The ring B is preferably an unsubstituted 6-membered homo- orheterocyclic ring.

The condensed ring formed by the rings A and B is preferably a ringrepresented by the formula:

In the “optionally substituted divalent C₁₋₆ aliphatic hydrocarbongroup” represented by Y in the above formula, the “divalent C₁₋₆aliphatic hydrocarbon group” includes, for example, C₁₋₆ alkylene (e.g.,methylene, ethylene, propylene etc.), C₂₋₆ alkenylene (e.g., vinyleneetc.) and C₂₋₆ alkynylene (e.g., ethenylene etc.).

The “substituent group” of the “optionally substituted divalent C₁₋₆aliphatic hydrocarbon group” includes, for example, C₁₋₆ alkyl (e.g.,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, hexyl etc.). The divalent C₁₋₆ aliphatic hydrocarbongroup may be substituted with 1 to 3 substituent groups at substitutablepositions, and when the number of substituent groups is 2 or more, therespective substituent groups may be the same or different.

Y is preferably a divalent C₁₋₆ aliphatic hydrocarbon group, morepreferably C₁₋₆ alkylene. (e.g., methylene etc.).

The “optionally substituted hydrocarbon group” represented by X in theabove formula and the number thereof are exemplified by those for the“optionally substituted hydrocarbon group” represented by R.

The “optionally substituted cyclic group” represented by X is notparticularly limited, and may be either an aromatic or non-aromaticcyclic group. Further, this cyclic group may be a homocyclic orheterocyclic ring. The heterocyclic ring is preferably the onecontaining S, N and/or O as a constituent atom of the ring. Further, thecyclic ring may be either a monocyclic or condensed ring. The number ofconstituent atoms in one ring is preferably 5 to 8. The “optionallysubstituted cyclic group” represented by X is particularly preferably anoptionally substituted ring-assembled aromatic group or an optionallysubstituted condensed aromatic group.

The “ring-assembled aromatic group” of the “optionally substitutedring-assembled aromatic group” refers to a group derived by removing anarbitrary hydrogen atom from an aromatic ring cluster wherein two ormore (preferably two or three) aromatic rings are directly bound via asingle bond and the number of direct bonds to the rings is smaller byone than the number of rings in the cyclic system. The “aromatic ring”includes an aromatic hydrocarbon, an aromatic heterocyclic ring etc.

The “aromatic hydrocarbon” includes, for example, a monocyclic orcondensed polycyclic (di- or tricyclic) aromatic hydrocarbon having 6 to14 carbon atoms (e.g., benzene, naphthalene, indene, anthracene etc.) orquinone having 6 to 14 carbon atoms (e.g., p-benzoquinone,1,4-naphthoquinone, indane-4,7-dione etc.).

The “aromatic heterocyclic ring” includes, for example, a 5- to14-membered, preferably 5- to 10-membered aromatic heterocyclic ringcontaining one or more (e.g., 1 to 4) heteroatoms selected from anitrogen atom, a sulfur atom and an oxygen atom in addition to thecarbon atoms. Specifically, the aromatic heterocyclic ring includesaromatic heterocyclic rings such as thiophene, benzothiophene,benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole,naphtho[2,3-b]thiophene, furan, phenoxathiine, pyrrole, imidazole,pyrazole, oxadiazole, pyridine, pyrazine, pyrimidine, pyridazine,indole, isoindole, 1H-indazole, purine, 4H-quinolizine, isoquinoline,quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline,cinnoline, carbazole, β-carboline, phenanthridine, acridine, phenazine,thiazole, isothiazole, phenothiazine, isoxazole, furazane, phenoxazine,phthalimide etc., as well as a ring formed by condensing these rings(preferably monocycles) with one or more (preferably one or two)aromatic rings (e.g., benzene ring etc.).

The aromatic ring cluster in which these aromatic rings are bounddirectly via a single bond includes, for example, an aromatic ringcluster formed from two or three (preferably two) rings selected from abenzene ring, a naphthalene ring and a 5- to 10-membered (preferably 5-or 6-membered) aromatic heterocyclic ring. Examples of the aromatic ringcluster includes biphenyl, 2-phenylnaphthalene, p-terphenyl,o-terphenyl, m-terphenyl, 2-phenylpyridine, 3-phenylpyridine,4-phenylpyridine, 2-phenylthiophene, 3-phenylthiophene, 2-phenylindole,3-phenylindole, 5-phenyloxadiazole etc. The aromatic ring cluster ispreferably an aromatic ring cluster consisting of 2 or 3 aromatic ringsselected from benzene, thiophene, pyridine, pyrimidine,1,2,4-oxadiazole, 1,3,4-oxadiazole, naphthalene and benzofuran.

Examples of the “ring-assembled aromatic group” include 2-biphenylyl,3-biphenylyl, 4-biphenylyl, 4-(2-thienyl)phenyl, 4-(3-thienyl)phenyl,3-(3-pyridyl)phenyl, 4-(3-pyridyl)phenyl, 6-phenyl-3-pyridyl,5-phenyl-1,3,4-oxadiazole-2-yl, 4-(2-naphthyl)phenyl,4-(2-benzofuranyl)phenyl etc. Among these, 2-biphenylyl, 3-biphenylyland 4-biphenylyl are preferred. 4-biphenylyl is particularly preferred.

The “substituent group” and the number thereof for the “optionallysubstituted ring-assembled aromatic group” are exemplified by those forthe “optionally substituted hydrocarbon group” represented by Rdescribed above.

For example, the “ring-assembled aromatic group” may have 1 to 5,preferably 1 to 3 of the above substituent groups at substitutablepositions in the ring-assembled aromatic group, and when the number ofsubstituent groups is 2 or more, the respective substituent groups maybe the same or different.

The “condensed aromatic group” of the “optionally substituted condensedaromatic group” refers to a monovalent group derived by removing anarbitrary hydrogen atom from a condensed polycyclic (preferably di- totetracyclic, preferably di- or tricyclic) aromatic ring. The “condensedpolycyclic aromatic ring” includes a condensed polycyclic aromatichydrocarbon, a condensed polycyclic aromatic heterocyclic ring etc.

The “condensed polycyclic aromatic hydrocarbon” includes, for example,condensed polycyclic (di- or tricyclic) aromatic hydrocarbons having 10to 14 carbon atoms (e.g., naphthalene, indene, anthracene etc.)

The “condensed polycyclic aromatic heterocyclic ring” includes, forexample, a 9- to 14-membered, preferably 9- to 10-membered condensedpolycyclic aromatic heterocyclic ring containing one or more (e.g., oneto four) heteroatoms selected from a nitrogen atom, a sulfur atom and anoxygen atom in addition to the carbon atoms. Examples thereof includearomatic heterocyclic rings such as benzofuran, benzimidazole,benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene,isoquinoline, quinoline, indole, quinoxaline, phenanthridine,phenothiazine, phenoxazine and phthalimide.

Examples of the “condensed aromatic group” include 1-naphthyl,2-naphthyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 2-benzofuranyl,2-benzothiazolyl, 2-benzimidazolyl, 1-indolyl, 2-indolyl, 3-indolyletc., preferably 1-naphthyl and 2-naphthyl.

The “substituent group” and the number thereof for the “optionallysubstituted condensed aromatic group” are exemplified by those for the“optionally substituted hydrocarbon group” represented by R above.

X is preferably an optionally substituted ring-assembled aromatic group.The ring-assembled aromatic group is more preferably a group consistingof 2 or 3 aromatic rings selected from benzene, thiophene, pyridine,pyrimidine, 1,2,4-oxadiazole, 1,3,4-oxadiazole, naphthalene andbenzofuran, and particularly 2-, 3- or 4-biphenylyl is preferred.

A preferable example of X is a ring-assembled aromatic group which mayhave one to three substituent groups selected from a halogen atom, C₁₋₃alkylene dioxy, nitro, cyano, optionally halogenated C₁₋₆ alkyl,optionally halogenated C₁₋₆ alkoxy, optionally halogenated C₁₋₆ alkylthio, hydroxy, amino, mono-C₁₋₆ alkylamino, di-C₁₋₆ alkylamino, 5- to7-membered saturated cyclic amino, formyl, carboxy, carbamoyl, C₁₋₆alkyl-carbonyl, C₁₋₆ alkoxy-carbonyl, C₆₋₁₀ aryl-carbonyl, C₆₋₁₀aryloxy-carbonyl, C₇₋₁₆ aralkyloxy-carbonyl, 5- or 6-memberedheterocyclic carbonyl, mono-C₁₋₆ alkyl-carbamoyl, di-C₁₋₆alkyl-carbamoyl, C₆₋₁₀ aryl-carbamoyl, 5- or 6-membered heterocycliccarbamoyl, C₁₋₆ alkylsulfonyl, C₆₋₁₀ arylsulfonyl, formylamino, C₁₋₆alkyl-carboxamide, C₆₋₁₀ aryl-carboxamide, C₁₋₆ alkoxy-carboxamide, C₁₋₆alkylsulfonylamino, C₁₋₆ alkyl-carbonyloxy, C₆₋₁₀ aryl-carbonyloxy, C₁ ₆alkoxy-carbonyloxy, mono-C₁₋₆ alkyl-carbamoyloxy, di-C₁₋₆alkyl-carbamoyloxy, C₆₋₁₀ aryl-carbamoyloxy, nicotinoyloxy and C₆ ₁₀aryloxy. Among these, more preferable is 2, 3- or 4-biphenylyl(preferably 4-biphenylyl) which may have 1 to 3 substituent groupsselected from a halogen atom, C₁₋₃ alkylene dioxy, nitro, cyano,optionally halogenated C₁₋₆ alkyl, optionally halogenated C₁₋₆ alkoxy,optionally halogenated C₁₋₆ alkylthio, hydroxy, amino, mono-C₁₋₆ alkylamino, di-C₁₋₆ alkyl amino, 5- to 7-membered saturated cyclic amino,formyl, carboxy, carbamoyl, C₁₋₆ alkyl-carbonyl, C₁₋₆ alkoxy-carbonyl,C₆₋₁₀ aryl-carbonyl, C₆₋₁₀ aryloxy-carbonyl, C₁₋₁₆ aralkyloxy-carbonyl,5- or 6-membered heterocyclic carbonyl, mono-C₁₋₆ alkyl-carbamoyl,di-C₁₋₆ alkyl-carbamoyl, C₆₋₁₀ aryl-carbamoyl, 5- or 6-memberedheterocyclic carbamoyl, C₁₋₆ alkylsulfonyl, C₆₋₁₀ arylsulfonyl,formylamino, C₁₋₆ alkyl-carboxamide, C₆₋₁₀ aryl-carboxamide, C₁₋₆alkoxy-carboxamide, C₁₋₆ alkylsulfonylamino, C₁₋₆ alkyl-carbonyloxy,C₆₋₁₀ aryl-carbonyloxy, C₁₋₆ alkoxy-carbonyloxy, mono-C₁₋₆alkyl-carbamoyloxy, di-C₁₋₆ alkyl-carbamoyloxy, C₆₋₁₀ aryl-carbamoyloxy,nicotinoyloxy and C6-10 aryloxy.

The “leaving group” represented by L in the formula above includes ahalogen atom (e.g., chloro, bromo, iodo etc.), optionally halogenatedC₁₋₆ alkyl sulfonyloxy (e.g., methanesulfonyloxy, ethanesulfonyloxy,trifluoromethanesulfonyloxy etc.), and optionally substituted C₆₋₁₀arylsulfonyloxy. In the “optionally substituted C₆₋₁₀ aryl sulfonyloxy”,the substituent group includes 1 to 3 groups selected from a halogenatom, optionally halogenated C₁₋₆ alkyl (e.g., C₁₋₆ alkyl which may have1 to 5 halogen atoms described above) and C₁₋₆ alkoxy (e.g., C₁₋₆ alkoxywhich may have 1 to 5 halogen atoms described above). Examples of the“optionally substituted C₆₋₁₀ arylsulfonyloxy” includebenzenesulfonyloxy, p-toluenesulfonyloxy, 1-naphthalenesulfonyloxy and2-naphthalenesulfonyloxy.

L is preferably a halogen atom.

As salts of the compounds represented by the formulae (I), (II), (IV)and (V), for example a salt with an inorganic base, an ammonium salt, asalt with an organic base, a salt with an inorganic acid, a salt with anorganic acid, and a salt with a basic or acidic amino acid are used.

Preferable examples of the salt with an inorganic base include, forexample, alkali metal salts such as sodium salt, potassium salt etc.;alkaline earth metal salts such as calcium salt, magnesium salt, bariumsalt etc.; and aluminum salts etc. Preferable examples of the salt withan organic base include, for example, salts with trimethylamine,triethylamine, pyridine, picoline, ethanolamine, diethanolamine,triethanolamine, dicyclohexylamine, N,N′-dibenzylethylenediamine etc.Preferable examples of the salt with an inorganic acid include, forexample, salts with hydrochloric acid, hydrobromic acid, nitric acid,sulfuric acid, phosphoric acid, etc. Preferable examples of the saltwith an organic acid include, for example, salts with formic acid,acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaricacid, maleic acid, citric acid, succinic acid, malic acid,methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid etc.Preferable examples of the salt with a basic amino acid include, forexample, salts with arginine, lysine, ornithine etc., and preferableexamples of the salt with an acidic amino acid include, for example,salts with aspartic acid, glutamic acid etc.

Among these salts, pharmaceutically acceptable salts are preferred. Forexample, when acidic functional groups are contained in the compound,inorganic salts such as alkali metal salts (for example, sodium salt,potassium salt etc.), alkaline earth metal salts (for example, calciumsalt, magnesium salt, barium salt etc.) or ammonium salts are used, andwhen basic functional groups are contained in the compound, inorganicsalts such as hydrochloride, sulfate, phosphate and hydrobromate ororganic salts such as acetate, maleate, fumarate, succinate,methanesulfonate, p-toluenesulfonate, citrate and tartrate are used.

In the process of the present invention, first the ether linkage of thecompound represented by the formula (I) or a salt thereof [also referredto hereinafter as Compound (I)] is selectively cleaved to produceCompound (II).

This reaction is carried out usually in the presence of an acid. Theacid used in this reaction includes, for example, mineral acids (e.g.,hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acidetc.), organic acids [e.g., acetic acid, propionic acid, butyric acid,sulfonic acid (e.g., methanesulfonic acid, ethanesulfonic acid,benzenesulfonic acid, toluenesulfonic acid, camphor sulfonic acid)etc.], Lewis acids (e.g., aluminum chloride, tin chloride, ironchloride, titanium chloride, boron trifluoride, boron trichloride etc.).In particular, Lewis acid and sulfonic acid (methanesulfonic acid) arepreferred.

Sometimes this reaction may proceed advantageously in the presence ofmercaptan or sulfide. Such mercaptan includes, for example, C₁ to C₈alkyl mercaptans (e.g., methyl mercaptan, ethyl mercaptan, propylmercaptan, isopropyl mercaptan, butyl mercaptan, isobutyl mercaptan,pentyl mercaptan, 2-pentyl mercaptan, neopentyl mercaptan, hexylmercaptan, heptyl mercaptan etc.), dimercaptans (e.g.,1,2-dimercaptoethane, 1,2-mercaptopropane, 1,3-dimercaptopropane,1,4-mercaptobutane, 1,5-mercaptopentane, 1,6-mercaptohexane etc.),mercaptoacids (e.g., mercaptoacetic acid, 2-mercaptopropionic acid,3-mercaptopropionic acid, 2-mercaptobutanoic acid etc.), mercaptoamines(e.g., 2-mercaptoethylamine, 3-mercaptopropylamine etc.), amino acids(e.g., cysteine etc.) and aromatic mercaptans (e.g., phenyl mercaptan,naphthyl mercaptan, p-chloromercaptan, mercaptoaniline etc.). Thesulfide includes, for example, optionally substituted C₁ to C₈ alkylsulfides (e.g., dimethylsulfide, ethylmethylsulfide, diethylsulfide,methylpropylsulfide, butylmethylsulfide, isopropylmethylsulfide,isobutylmethylsulfide, tert-butylmethylsulfide, 2-(methylthio)ethanol,4-methylthio-1-butanol, ethyl 2-hydroxyethylsulfide,chloromethylmethylsulfide, 2-chloroethylmethylsulfide, ethylenesulfide,propylenesulfide etc.), aromatic sulfides (e.g., diphenylsulfide,benzylphenylsulfide, methyl p-tolylsulfide, thioanisole,2-bromothioanisole, 4-bromothioanisole, 2-methylthioaniline,3-methylthioaniline etc.), amino acids (e.g., methionine etc.),disulfides (e.g., dimethyldisulfide, diethyldisulfide,dipropyldisulfide, dibutyldisulfide, diisopropyldisulfide,di-tert-butyldisulfide, ethylmethyldisulfide, methylpropyldisulfide,dicyclohexyldisulfide, benzylmethyldisulfide, benzyldisulfide,allyldisulfide, diphenyldisulfide, p-tolyldisulfide,difurfuryldisulfide, 2,2′-dihydroxy-6,6′-dinaphthyldisulfide,2-hydroxyethyldisulfide, 3,3-dithiopropionic acid, 4,4′-dithiobutanoicacid, cystine etc.). Among these, mercaptan is preferable, andmethionine is also preferably used.

In particular, a combination of methionine and methanesulfonic acid ispreferred.

This reaction is carried out usually in a solvent, and any solvents canbe used insofar as the reaction is not inhibited, and- such solventsinclude, for example, halogenated hydrocarbons (e.g., dichloromethane,chloroform, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane etc.),aromatic hydrocarbons (e.g., benzene, toluene, xylene, chlorobenzene,nitrobenzene etc.), ethers (e.g., ethyl ether, isopropyl ether,tetrahydrofuran, dioxane etc.), nitrites (e.g., acetonitrile,propionitrile etc.), esters (methyl acetate, ethyl acetate etc.) andalcohols (e.g., methanol, ethanol, propanol, isopropanol, butanol,methoxy ethanol etc.). These solvents can be used alone or incombination thereof in a suitable ratio. Further, the acid above mayalso be used as the solvent.

The amount of the acid used is 1 to 200 equivalents, preferably 1 to 50equivalents, relative to Compound (I).

When the reaction is carried out in the presence of mercaptan, theamount of mercaptan used is 1 to 100 equivalents, preferably 1 to 20equivalents, relative to Compound (I).

The reaction temperature is usually −30 to 200° C., preferably −10 to150° C.

The reaction time is usually 0.5 to 24 hours, preferably 1 to 10 hours.

Compound (III) thus obtained can be easily isolated by a means known inthe art, for example concentration, transfer to other solvent, solventextraction, crystallization etc., and the compound of higher purity canbe obtained by re-crystallization.

In the process of the present invention, Compound (II) is then reactedwith Compound (III) to produce Compound (IV).

This reaction is carried out usually in the presence of a base. As thebase, use is made of e.g. tertiary amines (e.g., trimethylamine,triethylamine, tributylamine, N-ethyl diisopropylamine, N-methylmorpholine etc.), aromatic amines (e.g., pyridine, picoline, quinoline,isoquinoline, N,N-dimethyl aniline, N,N-diethyl aniline etc.), alkalimetal carbonates (e.g., sodium bicarbonate, potassium carbonate, sodiumcarbonate, cesium carbonate etc.), alkali metal hydroxides (e.g.,potassium hydroxide, sodium hydroxide, calcium hydroxide etc.) andalkali metal alkoxides (e.g., potassium tert-butoxide, sodium methoxide,sodium ethoxide, sodium n-butoxide, sodium tert-butoxide etc.).

This reaction is carried out usually in a solvent, and any solvents canbe used insofar as the reaction is not inhibited, and such solventsinclude, for example, alcohols (e.g., methanol, ethanol, propanol,isopropanol, butanol, methoxyethanol etc.), halogenated hydrocarbons(for example, dichloromethane, chloroform, 1,2-dichloroethane,1,1,2,2-tetrachloroethane etc.), aromatic hydrocarbons (e.g., benzene,toluene, xylene, chlorobenzene, nitrobenzene, benzotrifluoride etc.),ethers (e.g., ethyl ether, isopropyl ether, tetrahydrofuran, dioxaneetc.), nitrites (e.g., acetonitrile, propionitrile etc.), esters (methylacetate, ethyl acetate etc.), N,N-dimethylformamide,N,N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide etc. Thesesolvents can be used alone or in combination thereof in a suitableratio.

The amount of Compound (III) used is 1 to 10 equivalents, preferably 1to 5 equivalents, relative to Compound (II).

The amount of the base used is 1 to 20 equivalents, preferably 1 to 5equivalents, relative to Compound (I).

The reaction temperature is usually −30 to 200° C., preferably −10 to150° C.

The reaction time is usually 0.5 to 24 hours, preferably 1 to 10 hours.

Compound (IV) thus obtained can be easily isolated by a means known inthe art, for example concentration, transfer to other solvent, solventextraction, crystallization etc., and the compound of higher purity canbe obtained by re-crystallization.

Then, the amide moiety of Compound (IV) is reduced to produce objectiveCompound (V).

The reducing agent used in this reaction includes, for example, metalhydrides (e.g., aluminum hydride, lithium. aluminum hydride, sodiumborohydride, lithium borohydride, lithium cyanoborohydride, sodiumdihydro-bis(2-methoxyethoxy)aluminate etc.), borane complexes (e.g., aborane-THF complex, catechol borane etc.), dibutyl aluminum hydride, anda mixture of these metal hydroxides and Lewis acids (e.g., aluminumchloride, titanium tetrachloride, cobalt chloride, boron trifluorideetc.).

This reaction is carried out usually in a solvent. The solvent may beany solvents insofar as the reaction is not inhibited, and use is madeof e.g. alcohols (e.g., methanol, ethanol, propanol, isopropanol,butanol, methoxyethanol etc.), halogenated hydrocarbons (e.g.,dichloromethane, chloroform, 1,2-dichloroethane,1,1,2,2-tetrachloroethane etc.), aromatic hydrocarbons (e.g., benzene,toluene, xylene, chlorobenzene, nitrobenzene, benzotrifluoride etc.) andethers (e.g., ethyl ether, isopropyl ether, tetrahydrofuran, dioxaneetc.). Two or more of these solvents may be used in combination in asuitable ratio.

The amount of the reducing agent used is 0.5 to 10 equivalents,preferably 1 to 5 equivalents, relative to Compound (IV).

The reaction temperature is usually −30 to 150° C., preferably −10 to120° C.

The reaction time is usually 0.5 to 24 hours, preferably 1 to 10 hours.

Compound (V) thus obtained can be easily isolated by a means known inthe art, for example concentration, transfer to other solvent, solventextraction, crystallization etc., and the compound of higher purity canbe obtained by re-crystallization.

In the production process described above, Compound (I) used as thestarting material can be produced by e.g. the following process.

Compound (VI) is subjected to amidation reaction to give Compound (I).

Compound (VI) is an easily available known compound, and examples of thesynthesis method include the methods described in JP-A 2-96552, JP-A6-206851 or Journal of Medicinal Chemistry, page 1326 (1989).

The method of synthesizing (1)1,2,3,4-tetrahydro-6-methoxynaphthalene-2-acetic acid as a typicalexample of Compound (VI) wherein R is methyl is described in e.g.Synthetic Communications, 11, 803-809 (1981), and the methods ofsynthesizing (2) 1,2,3,4-tetrahydro-6-methoxynaphthalene-2-carboxylicacid and 1,2,3,4-tetrahydro-6-methoxynaphthalene-2-butyric acid aredescribed in e.g. Journal of Chemical Society Perkin Transaction I,1889-1893 (1976).

The “amidation reaction” may be carried out in a method known in theart, for example, (1) Compound (III) is reacted with a compoundrepresented by the formula HNR¹R² in the present of a dehydrationcondensing agent, or (2) a reactive derivative of Compound (III) isreacted with a compound represented by the formula HNR¹R².

In the reaction (1) above, Compound (III), 1 to 5 equivalents of acompound represented by the formula HNR¹R² and 1 to 2 equivalents of adehydration condensing agent are reacted in an inert solvent at roomtemperature for 10 to 24 hours. If necessary, 1 to 1.5 equivalents of1-hydroxybenzotriazole (HOBT) and (or) 1 to 5 equivalents of a base(e.g., triethylamine etc.) may be added in the reaction mixture.

The “dehydration condensing agent” includes, for example,dicyclohexylcarbodiimide (DCC) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC). Inparticular, WSC is preferred.

As the inert solvent, for example, nitrile solvents (preferablyacetonitrile), amide solvents (preferably DMF), halogenated hydrocarbonsolvents (preferably dichloromethane), ether solvents (preferably THF)can be used alone or in combination thereof.

In the reaction (2) above, a reactive derivative of Compound (VI) and 1to 5 equivalents (preferably 1 to 3 equivalents) of a compoundrepresented by the formula HNR¹R² are reacted in an inert solvent at −20to 50° C. (preferably room temperature) for 5 minutes to 40 hours(preferably 1 to 18 hours). The reaction may be carried out if necessaryin the coexistence of 1 to 10 equivalents preferably 1 to 3 equivalentsof a base.

The “reactive derivative” of Compound (VI) includes acid halides (e.g.,acid chloride, acid bromide etc.), a mixed acid anhydrides (e.g., acidanhydrides thereof with C₁₋₆ alkyl-carboxylic acid, C₆₋₁₀aryl-carboxylic acid or C₁₋₆ alkyl carbonic acid) and active esters(e.g., esters thereof with optionally substituted phenol, 1-hydroxybenzotriazole or N-hydroxysuccinimide). The “substituent group” of the“optionally substituted phenol” includes one to five groups selectedfrom a halogen atom, nitro, optionally halogenated C₁₋₆ alkyl andoptionally halogenated C₁₋₆ alkoxy. The “optionally substituted phenol”includes, for example, phenol, pentachlorophenol, pentafluorophenol,p-nitrophenol etc. The reactive derivative is preferably an acid halide.

The “base” includes those bases exemplified in the process 1 above, andpreferable examples are potassium carbonate, sodium carbonate, sodiumhydroxide, potassium hydroxide, sodium bicarbonate, potassiumbicarbonate, triethylamine and pyridine.

As the inert solvent, for example an ether solvent, a halogenatedhydrocarbon solvent, an aromatic solvent, a nitrile solvent, an amidesolvent, a ketone solvent, a sulfoxide solvent, and water can be usedalone or as a mixture thereof. In particular, acetonitrile,dichloromethane and chloroform are preferred.

In Compound (V) obtained in the process of the present inventiondescribed above, (R)-(+)-6-(4-biphenylyl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin hydrochloride monohydrate [alsoreferred to hereinafter as Compound (V′)] is novel, is not denaturedeven after storage for a long time under usual conditions, and is veryexcellent in stability. Compound (V′) shows a diffraction pattern havingcharacteristic peaks in spacings (d values) of approximately 23.1,approximately 5.17, approximately 4.72, approximately 4.56,approximately 4.38, approximately 4.10, approximately 3.93,approximately 3.74, approximately 3.16 and approximately 3.09 angstromby powder X-ray crystal diffraction.

Compound (V′) has an excellent action of inhibiting the production andsecretion of β-amyloid protein, and is thus effective for preventing andtreating diseases attributable to β-amyloid protein.

Further, Compound (V′) is low toxic and excellent in transfer to thebrain.

Accordingly, Compound (V′) is useful as a safe agent for preventing andtreating diseases attributable to β-amyloid protein, particularly toproduction and secretion of β-amyloid protein, in mammals (e.g., rats,mice, guinea pigs, rabbits, sheep, horses, pigs, cattle, monkeys, humansetc.).

The diseases include diseases such as, for example, senile dementia,Alzheimer's disease, Down's syndrome and Parkinson's disease, amyloidangiopathy, and disturbance caused by β-amyloid protein at the time ofcerebrovascular disturbance, and Compound (V′) is particularlypreferably used against Alzheimer's disease.

Compound (V′) can be formed into a pharmaceutical preparation by meansknown in the art, and Compound (V′) can be safely administered orally orparenterally (for example, through topical, rectal or intravenousadministration) as it is or as a pharmaceutical composition in the formof e.g. tablets (including sugar-coated tablets, film-coated tablets),powders, granules, capsules (including soft capsules), solutions,injections, suppositories and sustained release agents prepared bysuitably mixing it with a suitable amount of pharmacologicallyacceptable excipients in the pharmaceutical manufacturing process.

The content of Compound (V′) in the pharmaceutical composition isusually about 0.1 to 100% by weight of the whole composition. The doseis varied depending on the subject of administration, administrationroute, intended diseases etc., and, for example, when used as the agentfor treating Alzheimer's disease, the active ingredient (Compound (V′))can be administered orally to an adult (approximately 60kg) in an amountof approximately 0.1 to 500 mg, preferably about 1 to 100 mg, morepreferably 5 to 100 mg in one portion, and may be administered in one toseveral divided portions a day.

The pharmaceutically acceptable carriers used in the production of thepharmaceutical composition include a wide variety of conventionalorganic or inorganic carrier materials as pharmaceutical materials, forexample, excipients, lubricants, binders or disintegrators in solidpreparations; solvents, solubilizers, suspension agents, isotonizingagents, buffers and analgesics in liquid preparations. If necessary,additives such as preservatives, antioxidants, coloring agents,sweeteners, adsorbents, wetting agent etc. can also be used.

The excipients used include, for example, lactose, white sugar,D-mannitol, starch, corn starch, microcrystalline cellulose and lightsilicic anhydride.

The lubricants used include, for example, magnesium stearate, calciumstearate, talc and colloidal silica.

The binders used include, for example, microcrystalline cellulose, whitesugar, D-mannitol, dextrin, hydroxypropylcellulose,hydroxypropylmethylcellulose, polyvinyl pyrrolidone, starch, sucrose,gelatin, methylcellulose, sodium carboxymethylcellulose etc.

The disintegrators used include, for example, starch,carboxymethylcellulose, calcium carboxymethylcellulose, sodiumcroscarmellose, sodium carboxymethyl starch, L-hydroxypropylcelluloseetc.

The solvents used include, for example, injection water, alcohol,propylene glycol, Macrogol, sesame oil, corn oil etc.

The solubilizers used include, for example, polyethylene glycol,propylene glycol, D-mannitol, benzyl benzoate, ethanol,trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodiumcitrate etc.

The suspension agents used include, for example, surfactants such asstearyl triethanolamine, sodium laurylsulfate, lauryl aminopropionicacid, lecithin, benzalconium chloride, benzethonium chloride andglycerine monostearate, and hydrophilic polymers such as polyvinylalcohol, polyvinyl pyrrolidone, sodium carboxymethylcellulose,methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose andhydroxypropylcellulose.

The isotonizing agents used include, for example, glucose, D-sorbitol,sodium chloride, glycerine, D-mannitol etc.

The buffers used include, for example, buffers such as phosphates,acetates, carbonates and citrates.

The analgesics used include, for example, benzyl alcohol etc.

The preservatives used include, for example, paraoxybenzoates,chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid,and soibic acid.

The antioxidants used include, for example, sulfites, ascorbic acid etc.

Hereinafter, the present invention is described by the followingReference Examples and Examples, which however are not intended to limitthe present invention.

REFERENCE EXAMPLE 1 2-(6-Methoxy-1-oxotetralin-2-ylidene)acetic acid

150 g of 6-methoxy-1-tetralone, 1812 g of 40% aqueous glyoxylic acid,2300 ml diglyme and 638 ml purified water were mixed. 283 ml conc.sulfuric acid was added dropwise thereto under stirring at roomtemperature, and then the mixture was stirred at 103 to 105° C. for 6hours. After the reaction solution was cooled with water and stirred for1 hour, the precipitated crystals were collected by filtration andwashed S times with 1.6 L purified water. By drying it under reducedpressure at 50° C., the title compound, 1215 g (yield 80.2%), wasobtained as pale brown yellow crystals.

¹H-NMR (300 MHz, CDCl₃) ppm; 2.98-3.03 (2H, m), 3.41-3.45 (2H, m), 3.89(3H, s), 6.73 (1H, d), 6.87-91 (2H, m) 8.09 (1H, d).

REFERENCE EXAMPLE 2 2-(6-Methoxy-1-oxotetralin-2-yl)acetic acid

1212 g of 2-(6-methoxy-1-oxotetralin-2-ilydene)acetic acid, 3636 mlacetic acid and 1357 ml purified water were mixed. 409 g zinc powder wasadded by small portions to this suspension, and the mixture was heatedunder reflux for 2 hours, and when the solution was hot, the zinc wasremoved by filtration. The vessel and the zinc were washed with 606 mlacetic acid of 80° C., and 2885 ml hot water was added dropwise to thefiltrate which was then cooled with water and stirred for 1 hour. Theprecipitated crystals were collected by filtration and washed 4 timeswith 1.45 L purified water. By drying it under reduced pressure at 50°C., the title compound, 1173 g (yield 95.9%), was obtained as brownyellow crystals.

¹H-NMR (300 MHz, DMSO) ppm; 1.92 (1H, m), 2.12 (1H, m), 2.38 (1H, m),2.72 (1H, m), 2.84-3.06 (3H, m), 3.84 (3H, s), 6.90 (2H, m), 7.84 (1H,m).

REFERENCE EXAMPLE 3 N,N-dimethyl-(6-methoxy-1-oxo-2-tetralin)acetamide

1170 g of 2-(6-methoxy-1-oxotetralone-2-yl)acetic acid, 7020 mlacetonitrile and 733 ml triethylamine were mixed. 645 ml pivaloylchloride was added dropwise thereto at 5 to 10° C. under a nitrogenatmosphere and stirred at the same temperature for 1 hour, then 611 gdimethylamine hydrochloride was added thereto, 1047 ml triethylamine wasadded dropwise thereto at 1 to 10° C., and the mixture was stirred atroom temperature. 3510 ml purified water was added to the reactionsolution, which was then extracted with 14.04 L ethyl acetate, and theorganic layer was washed twice with 3510 ml of 5% sodium bicarbonate andthen with 3510 ml purified water. The organic layer was concentratedunder reduced pressure such that the amount of the remaining solutionbecame 3510 g. The remaining solution was crystallized by adding 2750 mldiusopropyl ether, and 6030 ml diisopropyl ether was added dropwisethereto and stirred for 1 hour under cooling on ice. The precipitatedcrystals were collected by filtration, washed twice with 2.20 Ldiisopropyl ether and dried under reduced pressure at 50° C. to give1061 g of the title compound (yield 81.3%) as brown yellow crystals.

¹H-NMR (300 MHz, CDCl₃) ppm; 1.91 (1H, m), 2.26-3.34 (2H, m), 2.93 (1H,m), 2.99 (3H, s), 3.08 (3H, s), 3.10-3.21 (3H, m), 3.85 (3H, s), 6.68(1H, d), 6.81 (1H, m), 7.99 (1H, d).

REFERENCE EXAMPLE 4N,N-dimethyl-(1-hydroxy-6-methoxy-2-tetralin)acetamide

1056 g of N,N-dimethyl-(6-methoxy-1-oxo-2-tetralin)acetamide and 5280 mlmethanol were mixed, and a solution of 198.8 g sodium tetrahydroboratein 1190 ml dimethylacetamide was added dropwise thereto at 5 to 20° C.under a N₂ atmosphere, heated and stirred at an internal temperature of33 to 35° C. for 2.5 hours. The reaction solution was cooled andneutralized at 5 to 10° C. by dropping hydrochloricacid, then 5280 mlpurified water was added, the reaction solution was concentrated underreduced pressure until its volume was reduced by about half, 5280 mlpurified water was added to the remaining solution which was thenconcentrated again under reduced pressure such that the amount of theremaining solution became 5280 g. The precipitated crystals werecollected by filtration, washed with 2020 ml cold water and dried at 40°C. under reduced pressure, to give 870.8 g of the title compound as paleyellow crystals (yield 81.8%).

¹H-NMR (300 MHz, CDCl₃) ppm; 1.56-1.63 (1H, m), 1.93-1.97 (1H, m),2.25-2.28 (1H, m),2.28-2.46 (1H, m), 2.63-2.90 (3H, m), 2.98 (3H, s),3.04 (3H, s), 3.69 (1H, bs), 3.78 (3H, s) 4.43 (1H, d), 6.58-6.63 (1H,m), 6.74-6.79 (1H, m), 7.48 (1H, d).

REFERENCE EXAMPLE 5N,N-dimethyl-[6-methoxy-2-(3,4-dihydronaphthalene)]acetamide

866.0 g of N,N-dimethyl-(1-hydroxy-6-methoxy-2-tetralin)acetamide, 4330ml toluene and 17.3 g of p-toluenesulfonic acid hydrate were mixed andheated for 3 hours under reflux. The reaction solution was cooled toroom temperature, then washed twice with 2165 ml of 5% aqueous sodiumbicarbonate and then with 2165 ml purified water, and the organic layerwas concentrated under reduced pressure to give 764.7 g of the titlecompound (yield 94.8%).

¹H-NMR (300 MHz, CDCl₃) ppm; 2.30 (2H, t), 2.82 (2H, t) 2.98 (3H, s),3.04 (3H, s), 3.25 (2H, s), 3.79 (3H, s), 6.21 (1H, s), 6.65-6.68 (2H,m), 6.92 (1H, m).

REFERENCE EXAMPLE 6 (+)-N,N-dimethyl-(6-methoxy-2-tetralin)acetamide

0.338 g ofbis[[(S)-[2,2′-bis(diphenylphosphino)-1,1′-binaphthyl]]dichlororuthenium]triethylaminewas introduced into a 1-L autoclave which was then substituted withargon, and a solution of 190 gN,N-dimethyl-[6-methoxy-2-(3,4-dihydronaphthalene)]acetamide in 570 mLethanol was injected into the 1-L autoclave under argon pressure. Underhydrogen pressure kept at 5 MPa to 4 MPa, the mixture was reacted at 70°C. for 20 hours. The reaction solution was cooled to 30° C. and removedfrom the 1-L autoclave, followed by distilling the solvent away underreduced pressure, to give 285 g product. 630 mL diisopropyl ether wasadded thereto and subjected to azeotropic distillation until the amountof the remaining solution became 305 g. Then, 550 mL isopropyl ether wasadded to the remaining solution, the mixture was dissolved by heating at60° C., 9.5 g active carbon was added thereto and stirred at 60° C. for15 minutes, the active carbon was separated by filtration, and thefiltrate was stirred at room temperature. The precipitated crystals werecollected by filtration, washed with 190 mL diisopropyl ether and driedat 40° C. under reduced pressure, to give 163 g of the title compound aswhite crystals (yield 85%).

¹H-NMR (300 MHz, CDCl₃) ppm; 1.34-1.48 (m, 1H), 1.95-2.01 (m, 1H),2.29-2.46 (m, 4H), 2.79-2.91 (m, 3H), 2.97 (s, 3H), 3.02 (s, 3H), 3.76(s, 3H), 6.61-6.69 (m, 2H), 6.96 (d, 1H, J=8.3Hz).

EXAMPLE 1 (+)-N,N-dimethyl-(6-hydroxy-2-tetralin)acetamide

362.8 g of DL-methionine and 546.0 g of(+)-N,N-dimethyl-(6-methoxy-2-tetralin)acetamide were added by smallportions to 1638 mL methanesulfonic acid and dissolved. The solution wasreacted for 8 hours under heating at an internal temperature of 110° C.under a nitrogen atmosphere. The reaction solution was cooled to aninternal temperature of 10° C., and 2730 mL methanol, 1092 mL cold waterand 25% cold ammonium hydroxide were added thereto in this order toadjust its pH value to 7.0. After the reaction mixture was stirred at30° C. for 1 hour, the precipitated crystals were collected byfiltration and washed twice with 1640 mL mixture of methanol and tapwater (1:2). When the crystals were dried at 50° C. until their weightbecame constant, the title compound, 475.3 g (yield 87.7%), was obtainedas pale yellow crystals.

¹H-NMR (300 MHz, DMSO-d₆) δ: 1.32-1.36 (1H, m), 1.82-1.86 (1H, m),2.04-2.08 (1H, m), 2.22-2.32 (3H, m), 2.63-2.74 (3H, m), 2.83 (3H, s),2.96 (3H, s, 6.45-6.50 (2H, s), 6.79 (1H, d, J=8.1 Hz), 8.96 (1H, s).

EXAMPLE 2 (+)-N,N-dimethyl-(6-(4-biphenylyl)methoxy-2-tetralin)acetamide

378.6 g of 4-hydroxymethyl biphenyl was dissolved in 1133 ml DMF, and177.6 mL thionyl chloride was added dropwise thereto at an internaltemperature of 20° C. or less. The mixture was reacted at roomtemperature for 1.5 hours. 2267 mL ethyl acetate was added to thereaction solution and cooled at 10° C., and 1133 mL tap water was addeddropwise at 20° C. or less. The organic layer was separated and washedwith 1133 mL of 10% aqueous sodium carbonate, 1133 mL of 5% aqueoussodium bicarbonate and 1133 mL water in this order. The organic layerwas separated and concentrated under reduced pressure until the amountof the remaining solution became 763 g, then 872 mL DMF was addedthereto, and the reaction solution was concentrated under reducedpressure to distill the remaining ethyl acetate away, whereby 1286 gsolution of 4-chloromethyl biphenyl in DMF (content, 32.1%; yield,99.1%) was obtained. 435.9 g(+)-N,N-dimethyl-(6-hydroxy-2-tetralin)acetamide, 516.4 g potassiumcarbonate and 436 mL DMF were added thereto and stirred for 3 hours atan internal temperature of 80° C. under a nitrogen atmosphere. 1308 mLmethanol was added to the reaction solution, 1744 mL water was addedthereto at an internal temperature kept at about 60° C., and the mixturewas stirred at 60° C. for 30 minutes. Then, the reaction mixture wasstirred at 40° C. for 1 hour, and the precipitated crystals werecollected by filtration and washed with 1744 mL methanol and then twicewith 2180 mL water previously heated at 40° C. By drying the product at50° C. under reduced pressure, the title compound, 726.8 g (yield96.7%), was obtained as pale yellow crystals.

¹H-NMR (300 MHz, CDCl₃) δ: 1.42-1.48 (1H, m), 1.97-2.04 (1H, m),2.30-2.47 (4H, m), 2.79-2.91 (3H, m), 2.97 (3H, s) 3.01 (3H, s), 5.06(2H, s), 6.73-6.78 (2H, m), 6.97 (1H, d, J=8.3Hz), 7.34-7.62 (9H, m).

EXAMPLE 3(R)-(+)-(6-(4-biphenylyl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralinhydrochloride monohydrate

695 g of (+)-N,N-dimethyl-(6-(4-biphenylyl)methoxy-2-tetralin)acetamidewas suspended in 3475 mL toluene, and 562 g sodiumbis(2-methoxyethoxy)aluminate hydride(70% toluene solution) was addeddropwise thereto at an internal temperature of 20° C. or less in anitrogen atmosphere. The mixture was stirred for 1.5 hours at roomtemperature, then 695 mL of 4 N aqueous sodium hydroxide was addeddropwise at 20° C. or less, the mixture was stirred at room temperaturefor 30 minutes, and the organic layer was separated. Further, theorganic layer was washed twice with 695 mL of 1 N aqueous sodiumhydroxide and twice with 1390 mL water. 348 mL toluene was added to theorganic layer and heated at 60° C., and 175 mL conc. hydrochloric acid(content: 36%) was added dropwise thereto. The mixture was stirred for 1hour under cooling on ice, and the precipitated crystals were collectedby filtration and washed with 695 mL toluene and 1390 mL of 50% aqueousmethanol in this order. By drying the product at 40° C. under reducedpressure, the title compound, 723 g (yield: 94.4%), was obtained as paleyellow crystals. The powder X-ray crystal diffraction pattern is shownin FIG. 1 (measuring device: Rigaku RINT2500V (ultra X18) (Rigaku DenkiCo., Ltd.).

Data on powder x-ray crystal diffraction pattern Diffraction angle: 2θ(°) Spacing: d value (angstrom)  3.82 23.1  17.1 5.17 18.8 4.72 19.44.56 20.2 4.38 21.7 4.10 22.6 3.93 23.7 3.74 28.2 3.16 28.9 3.09 ¹H-NMR(300 MHz, DMSO-d₆) δ: 1.32-1.40(1H, m), 1.62-1.74(3H, m), 1.82-1.90(1H,m), 2.28-2.38(1H, m), 2.74(6H, s), 2.76-2.82(3H, br), 3.08-3.16(2H, m),5.09(2H, s), 6.72-6.80(2H, m), 6.96(1H, d, J=8.0Hz), 7.32-7.38(1H, m),7.44-7.54(4H, m), 7.64-7.72(4H, m), 10.4(1H, br).

EXAMPLE 4 Purification of(R)-(+)-(6-(4-biphenylyl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralinhydrochloride monohydrate

479.8 g of the crude(R)-(+)-(6-(4-biphenylyl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralinhydrochloride monohydrate obtained in Example 3 was dissolved in amixture of 3186 ml tetrahydrofuran and 864 ml water at 60° C. 24 gactive carbon was added thereto and stirred at 60° C. for 30 minutes.The active carbon was removed by filtration and washed with a mixture of336 ml tetrahydrofuran and 216 ml water. The filtrate was heated at 60°C., and 2688 ml tetrahydrofuran was added dropwise thereto understirring. The reaction solution was cooled to room temperature andstirred at 5 to 10° C. for 2 hours, and the precipitated crystals werecollected by centrifugation. The crystals were washed with a mixture of216 ml tetrahydrofuran and 744 ml water, to give the title compound in apure form (390.5 g, 85%).

INDUSTRIAL APPLICABILITY

Because the ether linkage is selectively cleaved without cleaving theamide linkage present in the same molecule and tertiary amines are notconverted into quaternary salts, the process of the invention is aconvenient and industrially advantageous process wherein aminederivatives of high qualities having the action of inhibiting thesecretion and accumulation of amyloid β protein can be produced in highyield.

What is claimed is:
 1. A process for producing a compound represented bythe formula:

wherein R¹ and R² each represent a hydrogen atom or an optionallysubstituted C₁₋₆ alkyl group, or may, together with their adjacentnitrogen atom, form an optionally substituted nitrogen-containingheterocyclic ring, ring A represents an optionally substituted benzenering, ring B represents an optionally substituted 4- to 8-membered ring,and Y represents an optionally substituted divalent C₁₋₆ aliphatichydrocarbon group, or a salt thereof, comprising selectively cleavingthe ether linkage of a compound represented by the formula:

wherein R represents an optionally substituted hydrocarbon group and theother symbols have the same meanings as defined above, or a salt thereofwherein the ether linkage is selectively cleaved in the presence of anacid and mercaptan or sulfide.
 2. The process according to claim 1,wherein the acid is Lewis acid.
 3. The process according to claim 1,wherein the acid is sulfonic acid.
 4. The process according to claim 1,wherein the ether linkage is selectively cleaved in the presence ofmethanesulfonic acid and methionine.
 5. The process according to claim1, wherein R is an optionally substituted C₁₋₆ alkyl or optionallysubstituted C₇₋₁₉ aralkyl group.
 6. The process according to claim 1,wherein the ether linkage of(+)-N,N-dimethyl-(6-methoxy-2-tetralin)acetamide is selectively cleaved,to produce (+)-N,N-dimethyl-(6-hydroxy-2-tetralin)acetamide.
 7. Aprocess for producing a compound represented by the formula:

wherein R¹ and R² each represent a hydrogen atom or an optionallysubstituted C₁₋₆ alkyl group, or may, together with their adjacentnitrogen atom, form an optionally substituted nitrogen-containingheterocyclic ring, ring A represents an optionally substituted benzenering, ring B represents an optionally substituted 4- to 8-membered ring,X represents an optionally substituted hydrocarbon group or anoptionally substituted cyclic group, and Y represents an optionallysubstituted divalent C₁₋₆ aliphatic hydrocarbon group, or a saltthereof, comprising selectively cleaving the ether linkage of a compoundrepresented by the formula:

wherein R represents an optionally substituted hydrocarbon group and theother symbols have the same meanings as defined above, or a salt thereofto produce a compound represented by the formula:

wherein the symbols have the same meanings as defined above, or a saltthereof, then reacting the same with a compound represented by theformula: X—L wherein X has the same meaning as defined above and Lrepresents an leaving group or a hydroxyl group, to produce a compoundrepresented by the formula

wherein the symbols have the same meanings as defined above, or a saltthereof wherein the ether linkage is selectively cleaved in the presenceof an acid and mercaptan or sulfide, and then subjecting the same toreduction reaction.
 8. The process according to claim 7, wherein X is anoptionally substituted ring-assembled aromatic group or an optionallysubstituted condensed aromatic group.
 9. The process according to claim7, which comprises selectively cleaving the ether linkage of(+)-N,N-dimethyl-(6methoxy-2-tetralin)acetamide, to produce(+)-N,N-dimethyl-(6-hydroxy-2-tetralin)acetamide, then reacting the samewith 4-chloromethylbiphenyl to produce(+)-N,N-dimethyl-(6-(4-biphenylyl)methoxy-2-tetralin)acetamide, and thensubjecting the same to reduction reaction, to produce(R)-(+)-6-(4-biphenylyl)methoxy-2-[2-N,N-dimethylamino)ethyl]tetralinhydrochloride monohydrate.
 10. A process for producing a compoundrepresented by the formula:

wherein R¹ and R² each represent a hydrogen atom or an optionallysubstituted C₁₋₆ alkyl group, or may, together with their adjacentnitrogen atom, form an optionally substituted nitrogen-containingheterocyclic ring, ring A represents an optionally substituted benzenering, ring B represents an optionally substituted 4- to 8-membered ring,X represents an optionally substituted hydrocarbon group or anoptionally substituted cyclic group, and Y represents an optionallysubstituted divalent C₁₋₆ aliphatic hydrocarbon group, or a saltthereof, comprising allowing a compound represented by the formula:

wherein the symbols have the same meanings as defined above, or a saltthereof to react with a compound represented by the formula:  X—Lwherein X has the same meaning as defined above and L represents anleaving group or a hydroxyl group, to produce a compound represented bythe formula:

wherein the symbols have the same meanings as defined above, or a saltthereof, and then subjecting the same to reduction reaction.